Sustained-release multi-granule tablet

ABSTRACT

A sustained-release multi-granule tablet is obtained by compressing sustained-release granules, which contains an active substance, and a formulation adjuvant. Each of the granules has been coated in advance with a layer of the formulation adjuvant and/or a layer of a mixture of the formulation adjuvant and the active substance. The tablet releases an active substance at a suitable velocity into the digestion tract, resulting in that the variability in the absorption of the drug in each patient and among individual patients is minimized to achieve maximum bioavailability.

This application is a continuation of now abandoned application Ser. No.07/895,464, filed Jun. 8, 1992, which was a continuation-in-part of nowabandoned application Ser. No. 07/752,987 filed on Sep. 3, 1991, whichwas a continuation of now abandoned application Ser. No. 07/595,732filed on Oct. 10, 1990, which was a continuation of abandonedapplication Ser. No. 07/240,343 filed on Aug. 25, 1988, which was acontinuation application of abandoned application Ser. No. 07/080,012filed on Jul. 31, 1987.

BACKGROUND OF THE INVENTION

1) Field of the Invention

This invention relates to a sustained-release multi-granule tabletuseful in the field of therapy. More specifically, this invention isconcerned with a tablet of the multiple unit type, in whichsustained-release granules are contained as a unit.

2) Description of the Prior Art

Sustained-release tablets are a preparation form that is intended toreduce the sufferance of patients by reducing the frequency ofadministration and at the same time to improve the usefulness of a drugto the maximum in view of both advantageous effects and side effects ofthe drug.

A certain type of sustained-release tablets take the form of theso-called multiple unit. Namely, a drug is firstly converted into asustained-release particulate or granular form by a suitable method. Apowdery or particulate substance composed of one or more formulationadjuvants is then mixed. The resulting mixture is finallycompression-formed or compressed into desired Weight, shape and size.

In a drug preparation of the multiple unit type, the drug is dividedinto a number of granules and is released as an active substance at asuitable velocity into the digestion tract so that the imbalance in theabsorption of the drug in each patient and among individual patients isminimized to achieve maximum bioavailability. As typical preparationforms, there are known for example spansule-type capsules in each ofwhich micropills are enclosed in a capsule and tablets of the multipleunit type. The present invention relates to the latter preparation form.

The following two problems have been recognized for many years asdrawbacks of tablets of the multiple unit type. The problem ofvariations in quality is mentioned first of all. In the case ofcompression-forming, it is generally known that inconsistent mixingoccurs due to differences in mixing ratio upon mixing operations,segregation caused by differences in granule number or shape amongincrements, etc. When tablets of the multiple unit type are producedfrom sustained-release granules, variations arise as to the contents ofthe sustained-release granules and the associated granules as aformulation aid by their numbers and their mixing ratio.

Regarding the above-mentioned problem, there is a study conducted by Dr.Shigeo Miwa ["Introduction to Chemical Engineering II", Chapter:"Mixing" (Asakura Shoten)]. From a theoretical curve between the numbersof granules of a drug administered and variation coefficients when themixing proportion of granules containing an active component is variedin various ways, it is indicated that the variation becomes smaller asthe proportion of granules containing the active component increases andthe number of granules administered increases.

The present inventors have contemplated how to reduce the variations byapplying the above theory to a drug preparation of the multiple unittype. If the proportion of granules containing the active component isincreased, the granules are however caused to agglomerate together upontheir compression forming and the granules hence become difficult todisperse at the time of the disintegration of the tablet, therebyleading to the loss of the inherent function of the multiple unit. Ifthe number of granules is increased on the other hand, another drawbackarises that the preparation form becomes greater.

As the second problem, granules undergo deformation or destruction byhigh-pressure compression at the time of compression-forming so that thesustained-release function of each unit granule is lost. This may beconsidered as the largest drawback of multiple unit tablets in a certainsense.

SUMMARY OF THE INVENTION

The present inventors have conducted an extensive research with a viewtoward developing a process for the formulation of multiple unit tabletswhich are free from occurrence of agglomeration of granules uponcompression forming, are small and have smaller variations in thecontent of an active component. As a result, it has been found thatsmall tablets of the multiple unit type having smaller variations in thecontent of an active component can be obtained by coating the surfacesof sustained-release granules as nuclei with layers of a formulationadjuvant and/or layers of a mixture of the formulation adjuvant and anactive substance and then compression-forming the thus coated granules.

In one aspect of this invention, it is thus provided a sustained-releasemulti-granule tablet obtained by compression-forming sustained-releasegranules, which contains an active substance, and a formulationadjuvant. Each of the granules has been coated in advance with a layerof the formulation adjuvant and/or a layer of a mixture of theformulation adjuvant and the active substance.

By coating the outer surfaces of sustained-release granules with aformulation aid or the like and forming protective coating filmsthereon, the discreteness of each granule can be enhanced so that theiragglomeration upon compression-forming or their deformation ordestruction can be avoided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 diagrammatically shows results of disintegration tests of TabletsA, B and C obtained by the coating method in comparison with results ofa disintegration test of a tablet obtained by adding powder;

FIG. 2 is also a diagrammatic representation of the results of thedisintegration tests of Tablets A, B and C in comparison with results ofa disintegration test of a tablet obtained by adding granules;

FIG. 3 diagrammatically illustrates results of disintegration tests ofTablets D, E and F in comparison with the results of the disintegrationtests of Tablets A, B and C; and

FIG. 4 diagrammatically depicts results of disintegration tests ofTablets G, H and I.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Illustrative examples of the formulation adjuvant in the presentinvention may include excipients, binders, disintegrators, etc. Asexemplary excipients useful in the practice of this invention, may bementioned Avicel 101, Avicel 301 and Avicel 102 (all trade names,crystalline celluloses), lactose, mannitol, sucrose, corn starch,dextrin, silicic acid, magnesium silicate, aluminum silicate, etc.

As exemplary binders, it is possible to use HPC-L (trade name,hydroxypropylcellulose), PVPK30 and PVPK90 (both trade names, polyvinylpyrrolidone), PEG6000 (trade name, polyethylene glycol),methylcellulose, etc.

As illustrative disintegrators, carboxy methyl cellulose calcium salt ofcarboxy methyl cellulose (CMC-Ca) sodium crosscarmelose and the like maybe used.

The preparation, coating and tablet making operations ofsustained-release granules in the present invention can be carried outrespectively by conventional procedures such as those mentioned below.

i) Preparation of granules (nuclear granules) to be used as nuclei:

Using a usual cylindrical granulator, nuclear granules are prepared inaccordance with the cyclindrical granulating method. That is, asustained-release granule is prepared using a conventional method froman active substance, i.e. the drug, and a sustained-release substance,e.g. sucrose-fatty acid ester, ethyl cellulose, methyl cellulose,polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, a gum arabic, gelatin and shellac.

ii) Coating in layers:

The coating is conducted by the rolling granulating method. Namely,nuclear granules and an excipient were mixed in a routine mixer such assuper mixer or Henschel mixer. The excipient is preferably awater-soluble or easily water-dispersible substance.

Upon coating, one or more formulation adjuvants such as binders,disintegrators and lubricants may also be added as needed. The lubricantmay be a conventional lubricant used in the preparation ofpharmaceutical tablets, for example, a running powder and the like suchas talc, magnesium stearate and the like.

iii) Tabletting:

Tabletting is conducted using a usual tablet machine. There are the wettabletting method and dry tabletting method. Tabletting may be effectedby either one of these methods. The size of the tablet is preferably inthe range of 0.5 to 2.5 mm. The size of the sustained-release nucleargranule is preferably in the range of 0.3 to 2 mm. The ratio ofexcipient to sustained-release nuclear granule is preferably about 20%by weight or more.

EXAMPLES

The constitution and advantageous effects of this invention willhereinafter be described specifically by the following Examples. Itshould however be borne in mind that the present invention is by nomeans limited by the following Examples.

Example 1

Sustained-release granules, which had been obtained by granulating in acylindrical granulating machine equipped with a screen of openings of0.5 mm across (Model: HV-G; manufactured by Hata Tekkosho K.K.) and thensifting the resultant granules to 16 mesh-60 mesh, were charged in a 1-lHenschel mixer. While mixing the granules with occasional addition ofcorn starch and an ethanol solution of PVP K30 in small quantities, thesustained-release granules were coated in layers to give the proportionsshown in Table 1.

                  TABLE 1                                                         ______________________________________                                        (All values indicate weight ratios)                                           Tablet            A       B         C                                         ______________________________________                                        Sustained-release granules                                                                      25      25        25                                        Corn starch       5       12.5      25                                        PVP K30           0.1     0.25      0.5                                       Corn starch/sustained-                                                                          20/100  50/100    100/100                                   release granules                                                              ______________________________________                                    

Two hundred milligram portions of the thus-obtained samples wereseparately weighed precisely and then compression-formed under 400kg/φ=8mm by a material testing machine (manufactured by Shimadzu Corp.),whereby tablets were obtained separately.

In the same manner as described above except for the omission of theethanol solution of PVP K30 as a binder, additional tablets wereseparately obtained by adding corn starch as is, i.e., in the form ofpowder or in the form of granules at the same ratio of corn starch tosustained-release granules.

Disintegration tests were then conducted with respect to thelayer-coated tablets (invention products), powder-added tablets andgranule-added tablets, all of which had been obtained above. Results areshown diagrammatically in FIGS. 1 and 2.

In each of the drawings, the ratio of corn starch to sustained-releasegranules is plotted along the axis of abscissas while the disintegrationtime is plotted in minutes along the axis of ordinates. Plotted pointshave the following significance:

◯ . . . Tablets by the layer-coated method (the method of thisinvention).

□ . . . Powder-added tablets.

Δ . . . Granule-added tablets. ##STR1##

In addition, coagulation tests were conducted with respect to thosetablets. Namely, each tablet was added with 10 ml of water in a weighingbottle. Twenty-four hours later, the disintegration residue wascollected by filtration. The coagulated matter (formed by coagulation oftwo or more granules) in the disintegration residue was then weighed.Results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        (All values are by wt. %)                                                     Corn starch/sustained-                                                                       20/100    50/100  100/100                                      release granules                                                              Layer-coated tablet                                                                          0         0       0                                            (this invention)                                                              Powder-added tablet                                                                          77.4      18.9    6.0                                          Granule-added tablet                                                                         76.3      67.4    34.2                                         ______________________________________                                    

From these results, it is understood that the tablets obtainedrespectively by the powder-adding method and the granule-adding methodare not different in disintegration time from the tablets formed solelyof the sustained release granules up to at least a cornstarch/sustained-release granule ratio of 50/100 but a significantreduction in disintegration time is observed at a cornstarch/sustained-release granule ratio as small as 20/100 in the case ofthe invention tablets obtained by the layer-coating method. It is alsoenvisaged that the layer-coating method permits the formulation oftablets without coagulation of sustained-release granules.

Example 2

Tablets D, E and F were obtained separately in the same manner as inExample 1 except that portions of corn starch in the respectivecompositions of Example 1 were replaced by a disintegrator, CMC-Ca, asshown in Table 3. Disintegration and coagulation tests were conductedwith respect to those tablets. Results of the disintegration tests willbe compared with those of Tablets A, B and C in Example 1.

                  TABLE 3                                                         ______________________________________                                        (All values indicate weight ratios)                                           Tablet           D          E       F                                         ______________________________________                                        Sustained-release granules                                                                     25         25      25                                        Corn starch      4.75       11.875  23.75                                     CMC-Ca           0.25       0.625   1.25                                      PVP K30          0.1        0.25    0.5                                       ______________________________________                                    

Results of the disintegration and coagulation tests are shown in FIG. 3and Table 4 respectively.

In FIG. 3, plotted points ◯ correspond respectively to Tablets D, E andF while plotted points  correspond respectively to Tablets A, B and Cof Example 1, namely, added with no CMC-Ca. Namely, the disintegrationtime of the sustained-release granules was shortened further by theaddition of a disintegrator such as CMC-Ca to the layer-coated granulesand moreover, no coagulation of the sustained-release granules wasobserved after their disintegration.

                  TABLE 4                                                         ______________________________________                                        (All values are by wt. %)                                                     Tablet              D         E     F                                         ______________________________________                                        Proportion of coagulated matter                                                                   0         0     0                                         ______________________________________                                    

Example 3

Tablets G, H and I were obtained in accordance with the composition ofExample 2 except that corn starch and CMC-Ca were changed respectivelyto lactose and sodium crosscarmelose. Disintegration and coagulationtests were conducted with respect to those tablets. Results are shown inFIG. 4 and Table 5 Respectively.

                  TABLE 5                                                         ______________________________________                                        (All values are by wt. %)                                                     Tablet              G         H     I                                         ______________________________________                                        Proportion of coagulated matter                                                                   0         0     0                                         ______________________________________                                    

Example 4

Sodium crosscarmelose, a disintegrator, was separately coated as layersin varied amounts on the surfaces of sustained-release granules. Aftercompression, the state of coagulation of the granules in each tablet wasobserved.

Namely, sodium crosscarmelose was coated as layers on the surface of thesustained-release granules in the same manner as in Examples 1-3. Then,200-mg portions of the thus-obtained samples were separately weighedprecisely and compression-formed under punching pressures of 200 kg and400 g/φ=8.0 mm by means of the material testing machine (manufactured byShimadzu Corp.).

Coagulation and disintegration tests were then conducted separately withrespect to the thus-obtained tablets. Compositions and test results areshown in Table 6.

                                      TABLE 6                                     __________________________________________________________________________    (All values are parts by weight unless otherwise specifically indicated)      Tablet                 J    K   L   M  N                                      __________________________________________________________________________    Composition                                                                   Sustained-release granules                                                                           25   25  25  25 25                                     Sodium Crosscarmelose  0    0.24                                                                              0.48                                                                              0.72                                                                             1.20                                   PVP K30                0    0.01                                                                              0.02                                                                              0.03                                                                             0.05                                   Test results                                                                  Coated layer/sustained-release granules (wt. %)                                                      0    1   2   3  5                                      Compression pressure                                                          200 kg                                                                        Proportion of coagulated                                                                             100  0   0   0  0                                      matter (wt. %)                                                                Disintegration time (min)                                                                            >60  53  34  21 10                                     Compression pressure                                                          400 kg                                                                        Proportion of coagulated                                                                             100  12  0   0  0                                      matter (wt. %)                                                                Disintegration time (min)                                                                            >60  >60 >42 25 18                                     __________________________________________________________________________

In Table 6, the sample obtained by compression-forming thesustained-release granules alone (Tablet J) did not disintegrate even 24hours later. In the case of the samples coated as layers with sodiumcross-carmelose on the other hand, no coagulation of thesustained-release granules was observed, for example, at a proportion ofthe coated layers of 1.0 wt.% and up when the compression pressure was200 kg/φ=8.0 mm.

In the case of Tablet G with about 20% of lactose added based on thesustained-release granules, the tablet did not disintegrate completelyand about two thirds remained undisintegrated even after an elapsed timeof 60 minutes later in the disintegration test. However, no coagulationamong the sustained-release granules was observed in the coagulationtest. It is hence appreciated that when lactose is added in a smallamount, the disintegration time becomes longer but no coagulation occursamong the sustained-release granules and the tablet undergoesdisintegration similar to that of a multiple unit.

Example 5

Using a 20-l Henschel mixer, portions of sustained-release granules wereseparately layer-coated to give mixing proportions (weight proportions)shown in Table 6. The formulation procedure of Examples 1-3 wasfollowed. Each portion of the sustained-release granules was charged inthe mixer. Thereafter, the excipients, disintegrator and binder werecoated as layers on the sustained-release granules while adding theirethanol solution little by little to the sustained-release granules.Results of disintegration and coagulation tests are also shown in Table7.

                  TABLE 7                                                         ______________________________________                                        (All figures are parts by weight                                              unless otherwise specifically indicated)                                      Tablet               P       Q                                                ______________________________________                                        Sustained-release granules                                                                         1000    1000                                             Avicel for drug and  475     --                                               food application                                                              Mannitol             --      950                                              CMC-Ca               25      50                                               PVP K30              10      20                                               Disintegration time (minutes)                                                                      36.0    19.5                                             Proportion of coagulated                                                                           0       0                                                matter (wt. %)                                                                ______________________________________                                    

Example 6

Tablets, which were able to show dispersion similar to that of multipleunits, were formulated by using sustained-release granules containingbunazosin hydrochloride as a basis. The sustained-release granules arecylindrical granules prepared by using a screen whose openings had adiameter of 0.5 mm. When the sustained-release granules werecompression-formed as they were, they did not integrate and did not showdispersion similar to that of multiple units.

Using a fluidized centrifugal granulator CF 360 (trade name;manufactured by Freund Sangyo K.K.), formulation adjuvants suspended in2400 ml of ethanol were added little by little so that they were causedto deposit as layers on the sustained-release granules containingbunazosin hydrochloride and the following composition was achieved.

    ______________________________________                                        Composition (parts by weight)                                                 ______________________________________                                        Sustained-release granules                                                                        750                                                       (content of bunazosin                                                         hydrochloride: 10%)                                                           Lactose             705                                                       CMC-Ca               30                                                       HPC-L                15                                                       ______________________________________                                    

The thus-obtained layer-coated granules were added with calcium stearatein an amount of 0.2 wt.%. Under punching conditions consisting of arevolution speed of 30 rpm and a compression pressure of 0.6-0.7ton/punch, the resultant mixture was then formed into tablets at a rateof 75 mg per tablet by punches having a diameter of 5.5 mm.

Results of disintegration and coagulation tests are as follows.

    ______________________________________                                        Test results                                                                  ______________________________________                                        Disintegration time  2.6-9.3 minutes                                          (6 tablets)                                                                   Proportion of coagulated                                                                           0 wt. %                                                  matter                                                                        ______________________________________                                    

In addition, a dissolution test was also conducted by the puddle method.Results are given below. The test was carried out under the followingconditions. Namely, the tablets were dissolved for 2 hours with thefirst solution of the Japan Pharmacopoeia and after adjustment of thepH, the dissolution was continued with the second solution of the JapanPharmacopoeia.

    ______________________________________                                        Results of the dissolution test:                                              Time (hours)                                                                             1        2      4       6    8                                     ______________________________________                                        wt. %      7.9      21.4   46.1    67.5 83.2                                  ______________________________________                                    

Example 7

In order to use coated layers as fast-acting portions of an activesubstance, bunazosin hydrochloride was added as an active substance inthe coated layers. Tablets were prepared by the same formulationprocedure and under the same formulation conditions as those employed inExample 5. Composition and respective test results are as follows:

    ______________________________________                                        Composition (parts by weight)                                                 Sustained-release granules                                                                      750                                                         (content of bunazosin                                                         hydrochloride: 8%)                                                            Bunazosin hydrochloride                                                                         15                                                          Lactose           690                                                         CMC-Ca            30                                                          HPC-L             15                                                          Results of disintegration and coagulation tests                               Disintegration time                                                                             9.4-11.8 minutes                                            (6 tablets)                                                                   Proportion of coagulated                                                                        0 wt. %                                                     matter                                                                        ______________________________________                                    

    ______________________________________                                        Results of the dissolution test:                                              Time (hours) 2      4          6    8                                         ______________________________________                                        wt. %        44.1   63.4       79.3 90.5                                      ______________________________________                                    

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

We claim:
 1. An improved oral pharmaceutical sustained-releasemulti-granule tablet, produced by a process which consists essentiallyof the steps of:preparing, as nuclear granules, a plurality ofsustained-release granules containing an active substance and asustained-release substance, wherein the active substance is bunazosinhydrochloride, and wherein the sustained-release substance is at leastone member selected from the group consisting of sucrose-fatty acidester, ethyl cellulose, methyl cellulose, polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, a gum arabic,gelatin and shellac; coating, in a laminate style, each of saidsustained-release granules with at least one layer composed of a firstformulation adjuvant or a mixture of the first formulation adjuvant andthe active substance, wherein the first formulation adjuvant comprises awater-soluble excipient; and compressing said coated sustained-releasegranules with a second formulation adjuvant comprising a lubricant toobtain the sustained-release multi-granule tablet.
 2. A tablet accordingto claim 1, wherein the water-soluble excipient is at least one memberselected from the group consisting of crystalline cellulose, lactose,mannitol, sucrose, corn starch, and dextrin.
 3. A tablet according toclaim 1, wherein the first or second formulation adjuvant or bothcontain at least one member selected from the group consisting ofbinders and disintegrators.
 4. A tablet according to claim 3, whereinthe binder is selected from the group consisting ofhydroxypropylcellulose, polyvinyl pyrrolidone, polyethylene glycol, andmethyl cellulose.
 5. A tablet according to claim 3, wherein thedisintegrator is selected from the group consisting of carboxy methylcellulose, calcium salt of carboxy methyl cellulose, and sodiumcrosscarmelose.
 6. A tablet according to claim 1, wherein each of saidsustained-release granules are coated with a plurality of layers of thefirst formulation adjuvant or the mixture of the first formulationadjuvant and the active substance.
 7. An improved oral pharmaceuticalsustained-release multi-granule tablet, comprising:a plurality ofsustained-release granules comprising an active substance and asustained-release substance, wherein the active substance is bunazosinhydrochloride, and wherein the sustained-release substance is at leastone member selected from the group consisting of sucrose-fatty acidester, ethyl cellulose, methyl cellulose, polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, a gum arabic,gelatin and shellac; each of said sustained-release granules having anouter coating comprising at least one layer composed of a firstformulation adjuvant or a mixture of the first formulation adjuvant andthe active substance, wherein the first formulation adjuvant is awater-soluble excipient; the plurality of granules and a secondformulation adjuvant comprising a lubricant being compressed in a tabletform.
 8. A tablet according to claim 1, wherein each of the granules iscoated in advance with an inner layer of the first formulation adjuvantand an outer layer of a mixture of the first formulation adjuvant andthe active substance.
 9. A tablet according to claim 1, wherein thefirst formulation adjuvant is crystalline cellulose, lactose, mannitol,sucrose, corn starch, dextrin, silicic acid, magnesium silicate oraluminum silicate.
 10. A tablet according to claim 7, wherein thewater-soluble excipient is at least one member selected from the groupconsisting of crystalline cellulose, lactose, mannitol, sucrose, cornstarch, and dextrin.
 11. A tablet according to claim 7, wherein thefirst or second formulation adjuvant or both contain at least one memberselected from the group consisting of binders and disintegrators.
 12. Atablet according to claim 11, wherein the binder is selected from thegroup consisting of hydroxypropylcellulose, polyvinyl pyrrolidone,polyethylene glycol, and methyl cellulose.
 13. A tablet according toclaim 11, wherein the disintegrator is selected from the groupconsisting of carboxy methyl cellulose, calcium salt of carboxy methylcellulose, and sodium crosscarmelose.
 14. A tablet according to claim 7,wherein each of said sustained-release granules are coated with aplurality of layers of the first formulation adjuvant or the mixture ofthe first formulation adjuvant and the active substance.